Based WHO classification system (American Journal of Surgical Pathology, 1997, 21(1): 114-121), lymphoid malignancies are grouped into three major classes: B-cell neoplasm, T-cell/natural killer (NK)-cell neoplasm and Hodgkin's lymphomas.
The B-cell neoplasm is further divided into two groups: precursor B-cell neoplasm and peripheral B-cell neoplasm. Precursor B-cell neoplasm includes precursor B-acute lymphoblastic leukemia (B cell-acute lymphoblastic leukemia, B-ALL)/lymphoblastic lymphoma (LBL). Peripheral B-cell neoplasm includes B-cell chronic lymphocytic leukemia (B-CLL), small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lympho plasmacytic lymphoma/immunocytoma, Mantle cell lymphoma, Follicular lymphoma, cutaneous follicular lymphoma, extranodal marginal zone B-cell lymphoma of MALT type, nodal marginal zone B-cell lymphoma (+/−monocytoid B-cells), splenic marginal zone lymphoma (+/−villous lymphocytes), hairy cell leukemia, plasmacytoma/plasma cell myeloma, diffuse large B-cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma and Burkift's lymphoma.
B-cell chronic lymphocytic leukemia (B-CLL) and B cell-acute lymphoblastic/lymphocytic leukemia (B-ALL) are two types of B cell leukemia. The B-CLL cells express CD19, CD5 and CD23 (Nicholas Chiorazzi, M.D., et al. N Engl. J Med 2005; 352:804-15). The B-ALL cells express CD19+CD10+ markers.
Small lymphocytic lymphoma is a B cell neoplasm. The monoclonal population of B cells in small lymphocytic lymphoma expresses CD19, CD5 and CD23 (Catherine Thieblemont, et al. Blood. 2004; 103:2727-2737).
Depending on the B-cell neoplasm diagnosed, current treatment options are chemotherapy, radiotherapy and immunotherapy.
CD40, expressed on the cell surface of normal B lymphocytes and dentritic cells, is a member of tumor necrosis factor receptor (TNFR) family. CD40L (CD154), expressed on T lymohocytes, is a member of tumor necrosis factor family (Castle B E, et al. J Immunol 1993; 151: 1777-1788). Interaction of CD40L and CD40 promotes the proliferation, differentiation and antigen presentation of B lymphocytes, dendritic cells and monocytes (Ranheim E A, et al. J Exp Med 1993; 177: 925-935; Yellin M J, et al. J Immunol 1994; 153: 666-674; Banchereau J, et al. Anhu Rev Immunol 1994; 12: 881-922; M. von Bergwelt-Baildon M S, et al. Blood 2002; 99: 3319-3325).
CD40 also expresses on the B cell neoplastic cells. It has been demonstrated that enhancing the CD40 expression promotes the apoptosis of B cell neoplastic cells (Peter Chu, et al. PNAS, March 19, 2002, vol. 99, no: 6 3854-3859; Frank Dicker, et al. BLOOD, 15 Apr. 2005 Volume 105, Number 8: 3193-3198).
Both in vitro and in vivo experiments indicated that stimulation and up-regulation of CD40 induced growth inhibition of B-cell neoplastic cells (Funakoshi et al., Blood 83: 2787-2794,1994; Murphy et al., Blood 86: 1946-1953,1995; Eliopoulos, A. G., et al. 1996. Oncogene 13:2243; Hirano, A., et al. 1999. Blood 93:2999; Tong, A. W., M et al. 2001.Clin. Cancer Res. 7:691).
Promoting CD40 expression on B cell neoplastic cells was reported to enhance the antigenicity of B cell neoplastic cells and consequently fostered the generation of cytotoxic T lymphocyte (CTL) specific to the cells. The CTL can efficiently kill B cell neoplastic cells (Dilloo D, et al. Blood. 1997; 90:1927-1933; Kato K, et al. J Clin Invest. 1998; 101:1133-1141; Wierda W G, et al. Blood. 2000; 96:2917-2924; Takahashi S, et al. Hum Gene Ther. 2001; 12:659-670; Takahashi S, et al. Cancer Gene Ther. 2001; 8:378-387). In the presence of CD40L, CD40 expressing B cell chronic lymphocytic leukemia cells can be killed by CD4 cytotoxic T lymphocytes (Frank Dicker, et al. Blood, 15 Apr. 2005 Vol 105, Num 8: 3193-3198). Interaction of D40L and CD40 on cells of Burkett's lymphoma could promote the cell to present tumor antigens to specific CTLs (Khanna, R. et al. 1997. J. Immunol. 159:5782). In vivo experiments and clinical trials also demonstrated that activation of CD40 could enhance the immunogenicity of B cell chronic lymphocytic leukemia (B-CLL) cell and consequently induce the generation of CTLs specific to the cells (Kato, K., et al. 1998. J. Clin. Invest. 101:1133; Wierda, W. G., et al. 2000. Blood 96: 2917).
Together, these data indicate that enhancing CD40 expression on B cell neoplastic cells can stimulate the anti-tumor immunity against B cell neoplasm. The anti-tumor immunity includes but not limits to the following:                1. promoting the apoptosis of B cell neoplastic cells;        2. inhibiting the growth of B cell neoplastic cells;        3. enhancing the immunogenicity of B cell neoplastic cells and therefore fostering the generation of CTLs specific to the cells.        
Interleukin-10 (IL-10) is a homodimer cytokine produced by certain T cells, monocytes, macrophages and some of neoplastic cells developed from B cells, T cells or NK cells (Kitabayashi et al., 1995; Masood et al., 1995; Sjoberg et al., 1996; Beatty et al., 1997; Boulland et al., 1998; Jones et al., 1999). IL-10 activity is mediated by its specific cell surface receptor. The receptor expresses on antigen-presenting cells, lymphocytes and also B-cell chronic lymphocytic leukemia (B-CLL) cells. It was found that addition of exogenous IL-10 inhibited the proliferation of B-CLL cells freshly isolated from patients (Jesper Jurlander, Chun-Fai Lai, Jimmy Tan, et al. Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells. Blood, Vol 89, No 11 (June 1), 1997: pp 4146-4152). IL-10 was also reported to inhibit the proliferation of B-CLL cells and enhance the apoptosis of B-CLL cells (Anne-Catherine Fluckiger, Isabelle Durand, and Jacques Banchereau. Interleukin 10 Induces Apoptotic Cell Death of B-Chronic Lymphocytic Leukemia Cells. J. Exp. Med. Volume 179 January 1994 91-99). Immunostimulating anticancer properties of IL-10 have been discussed in a review from which it is speculated that IL-10 over-expression within the tumor microenvironment may catalyze cancer immune rejection (Simone Mocellin, Francesco M. Marincola and Howard A. Young. Interleukin-10 and the immune response against cancer: a counterpoint. Journal of Leukocyte Biology. 2005; 78:1043-1051).
In the present invention, we provide an oligonucleotide and a method for treating B cell neoplasm by using the oligonucleotide of the present invention. The oligonucleotide induces the apoptosis of B cell neoplastic cells, promotes CD40 expression on B cell neoplastic cells and stimulates the B cell neoplastic cells to produce IL-10, which all contributes to the treatment of a B cell neoplasm.